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United States Department of Agriculture

Agricultural Research Service

Title: INCREASED BLOOD PRESSURE IN MICE LACKING CYTOCHROME P450 2J5)

Author
item Athirakul, Krairerk
item Bradbury, Alyce
item Graves, Joan
item Degraff, Laura
item Ma, Jixiang
item Zhao, Yun
item Couse, John
item Quigley, Raymond
item Harder, David
item Zhao, Xueying
item Imig, John
item Pedersen, Theresa
item Newman, John
item Hammock, Bruce
item Conley, Alan
item Korach, Kenneth
item Coffman, Thomas
item Zeldin, Darryl

Submitted to: Federation of American Societies for Experimental Biology Conference
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/24/2008
Publication Date: 12/22/2008
Publication URL: www.fasebj.org/content/22/12/4096.full.pdf+html
Citation: Athirakul, K., Bradbury, A.J., Graves, J.P., Degraff, L.M., Ma, J., Zhao, Y., Couse, J.F., Quigley, R., Harder, D.R., Zhao, X., Imig, J.D., Pedersen, T.L., Newman, J.W., Hammock, B.D., Conley, A.J., Korach, K.S., Coffman, T.M., Zeldin, D.C. 2008. INCREASED BLOOD PRESSURE IN MICE LACKING CYTOCHROME P450 2J5. Federation of American Societies for Experimental Biology Conference. 12):4096-108.

Interpretive Summary: The cytochrome P450 (CYP) enzymes participate in a wide range of biochemical functions including metabolism of arachidonic acid and steroid hormones. Mouse CYP2J5 is abundant in the kidney where its products, the cis-epoxyeicosatrienoic acids (EETs), modulate sodium transport and vascular tone. To define the physiological role of CYP2J5 in the kidney, knockout mice were generated using a conventional gene targeting approach. Cyp2j5 (-/-) mice develop normally and exhibit no overt renal pathology. While renal EET biosynthesis was apparently unaffected by the absence of CYP2J5, deficiency of this CYP in female mice was associated with increased blood pressure, enhanced proximal tubular transport rates, and exaggerated afferent arteriolar responses to angiotensin II and endothelin-1. Interestingly, plasma 17ß-estradiol levels were reduced in female Cyp2j5 (-/-) mice and estrogen replacement restored blood pressure and vascular responsiveness to normal levels. There was no evidence of enhanced estrogen metabolism, or altered expression or activities of steroidogenic hormones in female Cyp2j5 (-/-) mice, but their plasma levels of luteinizing hormone and follicle stimulating hormone were inappropriately low. Together, our findings illustrate a sex-specific role for CYP2J5 in regulation of blood pressure, proximal tubular transport and afferent arteriolar responsiveness via an estrogen-dependent mechanism.

Technical Abstract: The cytochrome P450 (CYP) enzymes participate in a wide range of biochemical functions including metabolism of arachidonic acid and steroid hormones. Mouse CYP2J5 is abundant in the kidney where its products, the cis-epoxyeicosatrienoic acids (EETs), modulate sodium transport and vascular tone. To define the physiological role of CYP2J5 in the kidney, knockout mice were generated using a conventional gene targeting approach. Cyp2j5 (-/-) mice develop normally and exhibit no overt renal pathology. While renal EET biosynthesis was apparently unaffected by the absence of CYP2J5, deficiency of this CYP in female mice was associated with increased blood pressure, enhanced proximal tubular transport rates, and exaggerated afferent arteriolar responses to angiotensin II and endothelin-1. Interestingly, plasma 17ß-estradiol levels were reduced in female Cyp2j5 (-/-) mice and estrogen replacement restored blood pressure and vascular responsiveness to normal levels. There was no evidence of enhanced estrogen metabolism, or altered expression or activities of steroidogenic hormones in female Cyp2j5 (-/-) mice, but their plasma levels of luteinizing hormone and follicle stimulating hormone were inappropriately low. Together, our findings illustrate a sex-specific role for CYP2J5 in regulation of blood pressure, proximal tubular transport and afferent arteriolar responsiveness via an estrogen-dependent mechanism.

Last Modified: 8/24/2016
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